Uveitis generally refers to intraocular inflammation and may, for example, affect the anterior portion of the uvea and/or the posterior portion of the uvea. Uveitis is a prevalent cause of visual impairment in many countries. The anterior portion of the uvea includes the iris and ciliary body. The posterior portion of the uvea includes the choroid. In addition to providing most of the blood supply of the intraocular structures, the uveal coat acts as a conduit for immune cells, particularly lymphocytes, to enter the eye. Consequently, it is directly involved in many intraocular inflammatory processes.
The International Uveitis Study Group classifies uveitis in terms of the eye(s) involved (i.e., unilateral or bilateral), course (i.e., acute, lasting less than 12 weeks, or chronic, lasting more than 12 weeks), and anatomical location in the eye (Bloch-Michel et al., Am J Ophthalmol., 103:234-235, 1987). Further standardization of the characterization and nomenclature of uveitis is provided by the SUN working group (Jabs, et al., Am J Ophtalmol., 140:509-516, 2005). Anterior uveitis includes, for example, iritis, anterior cyclitis, and iridocyclitis involving the iris and/or pars plicata (anterior ciliary body). Intermediate uveitis includes, for example, pars planitis, posterior cyclitis, hyalitis, and basal retinochoroiditis, referring to inflammation of the pars plana (posterior ciliary body) and/or adjacent peripheral retina. Posterior uveitis includes focal, multifocal, or diffuse choroiditis; retinitis; neuroretinitis, retinochoroiditis; and chorioretinitis; the latter 2 terms indicate which tissue appears primarily involved. Panuveitis refers to inflammation that involves both the anterior and posterior segments. Uveitis may be further classified on the presence or absence of granulomatous inflammation, marked by “mutton fat” keratic precipitates, iris nodules, and/or choroidal granulomas.
Estimates indicate that uveitis may account for about 10% of the visual handicaps in the western world (Nussenblatt, Int Ophthalmol., 14:303-308, 1990) and up to 15% of all cases of total blindness in the United States (Rothova et al., Br J Ophthalmol., 80:332-336, 1996). Legal blindness develops in at least one eye in 22% of all uveitis patients and in about 23% of all who require intraocular surgery. In addition, visual acuity loss to worse than 6/18 in at least one eye occurs in 35% of patients with uveitis, mainly as a result of persistent macular edema (Rothova et al., ibid). The ocular complications of uveitis are usually involved in the decrease in visual acuity.
IL-1β is a pro-inflammatory cytokine secreted by a number of different cell types including monocytes and macrophages. When released as part of an inflammatory reaction, IL-1β produces a range of biological effects, mainly mediated through induction of other inflammatory mediators such as corticotrophin, platelet factor-4, prostaglandin E2 (PGE2), IL-6, and IL-8. IL-1β induces both local and systemic inflammatory effects through the activation of the IL-1 receptor found on almost all cell types. The interleukin-1 (IL-1) family of cytokines has been implicated in a number of disease states. IL-1 family members include IL-1α, IL-1β, and IL-1Ra. Although related by their ability to bind to IL-1 receptors (IL-1R1 and IL-1R2), each of these cytokines is different, being expressed by a different gene and having a different primary amino acid sequence. Furthermore, the physiological activities of these cytokines can be distinguished from each other.
Effective treatment of uveitis, including an acute uveitis exacerbation (e.g., uveitis flare, uveitis attack), with a complete resolution of inflammatory findings, is important for a better visual outcome. The longer a uveitis exacerbation goes unresolved, the greater are the chances of more severe sequela, incomplete resolution, and/or loss of vision. There remains a need for effective methods of treating and preventing uveitis, including treatment of refractory uveitis and prevention of uveitis exacerbations including in at risk subjects.